DISEASES OF THE CENTRAL NERVOUS SYSTEM Hisham Alkhalidi

Infections of the central nervous system Portals of entry of infection into the CNS – Hematogenous spread the most common means of entry – Direct implantation of microorganisms traumatic or in congenital CNS malformation – Local extension occurs secondary to an established infection in a near by organ (air sinus, an infected tooth or middle ear) – Through the peripheral nervous system into the CNS certain viruses, such as rabies and herpes zoster.

Meningitis An inflammatory process of the leptomeninges and CSF within the subarachnoid space.

Pyogenic meningitis Medical emergency The causative microorganisms: – Neonates and infants: Escherichia coli, Listeria and the group B streptococci – Older infants,children's, adolescents and in young adults: Streptococcus pneumoniae,Neisseria meningitidis (Meningococcal meningitis) and Haemophilus influenzae – Elderly, immunecompromised patients & neonates : listeria monocytogens – S. aureus and gram negative rods are common after placement of surgical shunts

Pyogenic meningitis CSF Findings in spinal tap – cloudy or frankly purulent CSF – as many as 90,000 neutrophils /mm – a raised protein level – a markedly reduced glucose content – Bacteria may be seen on a Gram stained smear or can be cultured, sometimes a few hours before the neutrophils appear

Acute meningitis PHOTO: Gross picture

Clinical Features Systemic signs of infection With meningeal irritation signs and neurologic impairment Headache, photophobia, irritability, clouding of consciousness and neck stiffness Untreated, pyogenic meningitis can be fatal Effective antimicrobial agents markedly reduce mortality associated with meningitis

Complications Phlebitis, that may also lead to venous occlusion and hemorrhagic infarction of the underlying brain Leptomeningeal fibrosis and consequent hydrocephalus Septicemia with hemorrhagic infarction of the adrenal glands and cutaneous petechiae (known as Waterhouse- Friderichsen syndrome, particularly common with meningococcal and pneumococcal meningitis) Focal cerebritis & seizures Cerebral abscess Cognitive deficit Deafness

Brain abscess May arise from: – Direct implantation of organisms – Local extension from adjacent foci (mastoiditis, paranasal sinusitis) – Hematogenous spread (usually from a primary site in the heart, lungs, distal bones or after tooth extraction) Streptococci and staphylococci are the most common organisms identified in non immunosuppressed populations Predisposing conditions: – Acute bacterial endocarditis (usually give multiple microabscesses) – Cyanotic congenital heart disease in which there is a right-to-left shunt – Loss of pulmonary filtration of organisms ( e.g. chronic pulmonary sepsis, bronchiectasis) Most common on cerebral hemispheres

Brain abscess Morphologically, – it is composed of liquefactive necrosis – The surrounding brain is edematous, congested & contains reactive astrocytes & perivascular inflammatory cells. Present clinically with progressive focal neurologic deficits in addition to the general signs of raised intracranial pressure The CSF – Contain only scanty cells – ↑ protein – Normal level of glucose Complications of Brain abscess: – Herniation – Rupture of abscess into subarachnoid space or ventricle

Tuberculosis The subarachnoid space contains a gelatinous or fibrinous exudate, most often at the base of the brain Tuberculoma is well-circumscribed intraparenchymal mass Rupture of tuberculoma into subarachnoid space results in tuberculus meningitis, & may present as acute or chronic A tuberculoma may be up to several centimeters in diameter, causing significant mass effect Always occurs after hematogenous dissemination of organism from primary pulmonary infection On microscopic examination, there is usually a central core of caseous necrosis surrounded by a typical tuberculous granulomatous reaction

CSF in TB There is only a moderate increase in cellularity of the CSF (pleiocytosis) made up of mononuclear cells, or a mixture of polymorphonuclear and mononuclear cells The protein level is elevated, often strikingly so The glucose content typically is moderately reduced or normal

Fungal infection Candida albicans, Mucor, Aspergillus fumigatus, and Cryptococcus neoformans are the most common fungi that can cause encephalitis Parenchymal invasion, usually in the form of granulomas or abscesses, can occur with most of the fungi and often coexists with a meningitis

Cryptococcal meningitis and meningoencephalitis – Observed often in association with AIDS. It can be fulminant and fatal in as little as 2 weeks, or indolent, or it can evolve over months or years

Toxoplasmosis Causative organisms: Toxoplasma gondii The clinical symptoms are subacute, evolving during a 1- or 2-week period, and may be both focal and diffuse Ingestion of raw or partly cooked meat, especially pork, lamb, and Ingestion of contaminated cat faeces Transplacental transmission --> severe brain injury in neonate (Neonatal hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, blindness, epilepsy, psychomotor or mental retardation, Rare classic triad - Chorioretinitis, hydrocephalus, cerebral calcifications) Most common causes of neurologic symptoms and morbidity in patients with AIDS (40%) -Necrotizing encephalitis-and in immunocompromised Pt. Ocular toxoplasmosis (chorioretinitis)

Viral infections The most common cause of encephalitis Almost invariably associated with meningeal inflammation General features: Perivascular inflammatory infiltrates(mononuclear cells) Microglial nodules Inclusion bodies

PHOTO: viral encephalitis

Herpes simplex encephalitis – HSV type 1 encephalitis causes hemorrhagic necrosis of temporal lobes & orbital frontal areas – Most common in children and young adults – Cowdry type A intranuclear viral inclusion bodies can be found in both neurons and glia

HIV infection HIV patients are prone of multiple diseases that can affect the CNS, PNS and the skeletal muscle. Infection is just an example. Patients affected with HIV encephalitis with dementia referred to as AIDS-dementia complex The dementia begins insidiously, with mental slowing, memory loss, and mood disturbances, such as apathy and depression Motor abnormalities, ataxia, bladder and bowel incontinence and seizures can also be present

Morphology, HIV encephalitis On macroscopic examination: – the meninges are clear, and there is some ventricular dilation with sulcal widening but normal cortical thickness Microscopically: – a chronic inflammatory reaction with widely distributed infiltrates of microglial nodules, sometimes with associated foci of tissue necrosis and reactive gliosis. – multinucleated giant cell the hallmark of HIV encephalitis

Prion diseases A group of neurodegenerative conditions characterized clinically by slowly progressive ataxia and dementia and pathologically by accumulations of fibrillar or insoluble prion proteins, degeneration of neurons, and vacuolization, termed spongiform degeneration Group of diseases includes in humans: – Creutzfeldt-Jakob disease (CJD),Gerstmann-Sträussler-Scheinker syndrome (GSS) – Fatal familial insomnia, bovine spongiform encephalopathy (BSE)" mad cow disease" They are all associated with abnormal forms of a specific protein, termed prion protein (PrP)

PHOTO: Prion disease mechanism

Prion diseases Pathogenesis : Unique diseases can be genetic, sporadic or infectious – Misfolding or conformational change of the normal prion protein (PrP c ) converts it to an insoluble, protease resistant isoform PrP sc. which precipitates as amyloid.(amyloid- rich deposited known as Kuru plaques) – Loss of function of (PrP c ) or toxicity of PrP sc. cause neuronal degeneration and loss by unknown mechanism. – Transmitted via ingestion of infected foodstuffs and via iatrogenic means (e.g. blood transfusion, Instrument,GH)

Prion diseases Creutzfeldt-Jakob Disease/Sub acute Spongiform Encephalopathies: (the most common human form) – A rare but well-characterized disease that have long incubation period and manifests clinically as a rapidly progressive dementia and diffuse atrophy of the brain. – It is primarily sporadic (about 85% of cases) in its occurrence – Familial forms also exist (15% of cases are autosomal dominant) – The disease has a peak incidence in the seventh decade. – There are well-established cases of iatrogenic transmission, notably by corneal transplantation, deep implantation of neural electrodes, and contaminated preparations of human growth hormone – Inflammatory infiltrates are usually absent – The disease is uniformly fatal, with an average duration of only 7 months

Tumours of the CNS General concepts: – Histological distinction between benign and malignant lesions may be more subtle – The anatomic site of the neoplasm can have lethal consequences irrespective of histological classification – The pattern of spread of primary CNS neoplasms differs from that of other tumors: rarely metastasize outside the CNS the subarachnoid space does provide a pathway for spread

General manifestations Seizures, headaches, vague symptoms Focal neurologic deficits related to the anatomic site of involvement Rate of growth may correlate with history

CNS tumors May arise from: – cells of the coverings (meningiomas) – cells intrinsic to the brain (gliomas, neuronal tumors, choroid plexus tumors) – other cell populations within the skull (primary CNS lymphoma, germ-cell tumors) – they may spread from elsewhere in the body (metastases)

Tumours of the CNS Gliomas: – Astrocytomas – Oligodendrogliomas – Ependymomas

Astrocytomas Fibrillary: – 4 th to 6 th decade – Commonly cerebral hemisphere – Variable grades: Diffuse astrocytoma Anaplstic astrocytoma Glioblastoma Pilocytic – Children and young adults – Commonly cerebellum – Relatively benign

Fibrillary Astrocytoma Well differentiated “diffuse astrocytoma” ( WHO grade II) : – Static or progress slowly (mean survival of more than 5 years) – Moderate cellularity – Variable nuclear pleomorphism Less differentiated (higher-grade) : – Anaplstiac astrocytoma ( WHO grade III) More cellular Greater nuclear pelomrophism Mitosis – Glioblastoma ( WHO grade IV) With treatment, mean survival of 8-10 months Necrosis and/or vascular or endothelial cell proliferation

Note that diffuse astrocytoma are poorly demarcated

GBM – Pseudopalisading necrosis AND/OR – Vascular proliferation

Genetics In addition to other markers, it became clear that secondary glioblastomas shared p53 mutations that characterized low- grade gliomas While primary glioblastomas were characterized by amplification of the epidermal growth factor receptor (EGFR) gene

Pilocytic Astrocytoma Often cystic, with a mural nodule Well circumscribed "hairlike“=pilocytic processes that are GFAP positive Rosenthal fibers & hyaline granular bodies are often present Necrosis and mitoses are typically absent

Oligodendroglioma The most common genetic findings are loss of heterozygosity for chromosomes 1p and 19q Fourth and fifth decades Cerebral hemispheres, with a predilection for white matter Better prognosis than do patients with astrocytomas (5 to 10 years with Rx) Anaplastic form do worse

In oligodendroglioma tumor cells have round nuclei, often with a cytoplasmic halo Blood vessels in the background are thin and can form an interlacing pattern

Ependymoma Most often arise next to the ependyma-lined ventricular system, including the central canal of the spinal cord The first two decades of life, they typically occur near the fourth ventricle In adults, the spinal cord is their most common location

Tumor cells may form round or elongated structures (rosettes, canals) perivascular pseudo-rosettes Anaplastic ependymomas show increased cell density, high mitotic rates, necrosis and less evident ependymal differentiation

Tumours of the CNS Meningioma: – Predominantly benign tumors of adults – Origin: meningothelial cell of the arachnoid

Well demarcated Attached to the dura with compression of underlying brain Whorled pattern of cell growth and psammoma bodies

Main subtypes: – Syncytial – Fibroblastic – Transitional Also note: – Atypical meningiomas – Anaplastic (malignant) meningiomas

Medulloblastoma Children and exclusively in the cerebellum Neuronal and glial markers may be expressed, but the tumor is often largely undifferentiated The tumor is highly malignant, and the prognosis for untreated patients is dismal; however, it is exquisitely radiosensitive With total excision and radiation, the 5-year survival rate may be as high as 75%

extremely cellular, with sheets of anaplastic ("small blue") cells small, with little cytoplasm and hyperchromatic nuclei; mitoses are abundant.

Haemangioblastoma Commonly cerebellar tumor Aslo the retina and others Can occur in association with Von Hippel-Lindau Disease (cyst in pancreas, liver & kideny and renal cell carcinoma) Highly vascular neoplasm that occurs as a mural nodule associated with a large fluid-filled cyst Intervening stromal cells of uncertain histogenesis characterized by vacuolations

Schwannoma They are often encountered within the cranial vault, in the cerebellopontine angle, where they are attached to the vestibular branch of the eighth nerve (tinnitus and hearing loss)

Sporadic schwannomas are associated with mutations in the NF2 gene Bilateral acoustic schwannoma is associated with NF2 Attached to the nerve but can be separated from it

Cellular Antoni A pattern and less cellular Antoni B nuclear-free zones of processes that lie between the regions of nuclear palisading are termed Verocay bodies

Neurofibroma Examples: (cutaneous neurofibroma) or in peripheral nerve (solitary neurofibroma) These arise sporadically or in association with type 1 neurofibroma, rarely malignant plexiform neurofibroma, mostly arising in individuals with NF1, potential malignancy Neurofibromas cannot be separated from nerve trunk (in comparison to shcwannoma)

Metastatic tumours – About half to three-quarters are primary tumors, and the rest are metastatic – Lung, breast, skin (melanoma), kidney, and gastrointestinal tract are the commonest